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Sunday, March 25, 2012

Some drugs just never go away< but they should

We first criticized this drug in 2006, when in the BMJ we first mooted rosiglitazone
in the DREAM trial – which cost $23million - caused a significant
increase in heart failure, despite the population being at low risk of
such a problem. The drug showed no clear benefit at 3 years on clinical
outcomes and the rate of all cardiovascular events tended to be higher
in the treatment group.
What happened after that was good news, in that Steven Nissen in 2007
from the Cleveland Clinic undertook a systematic review of the effects
of rosiglitazone, combining results from a total of 42 trials. The
results clearly showed rosiglitizone was associated with a significant
increase in the risk of heart attack and death confirming what we had
suspected. Around the same time a Cochrane review
also found there was no evidence of any benefits with the drug over
other available treatments for diabetes and, because of side effects
such as edema, fractures, and possible increased risk of MI, recommended
other antidiabetic medications be used in preference.
The uses of composite end points in the DREAM trial were also aptly
criticized by Victor Montori
in the BMJ. These drugs were making significant inroads in the drug
market with more than 1.5 million prescriptions for rosiglitazone and
pioglitazone issued in England alone in 2007.
The week of the 5th of June, to my surprise the Lancet published the RECORD trial
of rosiglitazone as an oral agent combination therapy. In English that
means they combined it with another therapy. What they showed is
rosiglitazone increased heart failure; but they then went on to report
it doesn’t reduce cardiovascular death and the data was inconclusive on
myocardial infarction rates. This is one of those interpretations
designed to keep the drug on the market. Highly marketing driven and
usually highly dangerous.
A couple of points however are worth noting: more people were on a
statin (9%) in the rosiglitazone group, they had an excess of heart
attack, and although this was not significant it adds to the findings in
the Nissen systematic review. Also, in the subgroup of RECORD patients
with pre-existing heart disease, there was a 26% increase in heart
attack. In addition, it seems the treatment also raises the risk of
fractures.
Finally, the RECORD trial had an unexpected low event rate, 2.5 % per
year, whilst the trial was powered on an expected event rate of 11% per
year; taken together with losses of 3% per year leads to very
significant concerns about the results. The final nail in the coffin of
this drug is that at the time of Nissen’s original review, approximately
30% of patients in the trial assigned to receive rosiglitazone had
stopped taking the drug. By the time of the recent Lancet publication
there is no mention of how many were actually on the drug. This is a no
brainer, how can you assess the safety of a drug if you can’t tell who
is actually taking it.